Phencyclidine metabolite irreversible binding in the rat: gonadal steroid regulation and CYP2C11

These studies were conducted to determine the effect of hormones on sex-related differences in phencyclidine (PCP) metabolite irreversible binding and to determine the cytochrome P450 isoform(s) involved in this process. Sprague-Dawley male rats were castrated or administered estradiol and Sprague-Dawley female rats were ovarectomized or ovarectomized and given testosterone. Liver microsomal metabolism studies demonstrated that PCP metabolite binding to proteins was significantly altered by testosterone and estrogen administration. Castration of male rats decreased metabolite binding to 57% of sham-operated male levels, and administration of testosterone to ovarectomized female rats increased metabolite binding to 41 % of normal male levels. No metabolite adducts could be detected in microsomes from male rats administered estradiol or from sham-operated females given vehicle. These hormone-induced changes in metabolite binding closely matched the hormone-induced changes in CYP2C11 function and expression in these same microsomes. PCP metabolite irreversible binding to microsomal proteins was highly correlated with CYP2C11 function (as assessed by the formation of 2alpha-OH-testosterone, r = 0.91) and with CYP2C11 expression (as assessed by Western blot analysis, r = 0.95). In addition, an anti-CYP2C11 monoclonal antibody almost completely inhibited PCP metabolite binding (down to 7% of control male values) in an antibody concentration-dependent manner. These data strongly implicate CYP2C11 as an isoform involved in PCP metabolism and the formation and/or binding of a reactive PCP metabolite to microsomal proteins.